Coating construct containing poly(vinyl alcohol)

ABSTRACT

A method of forming a surface layer that includes a hydroxyl polymer on a substrate coating on a medical device is provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional application of U.S. application Ser. No.11/365,392, filed on Feb. 28, 2006, the teaching of which isincorporated herein in its entirety by reference.

FIELD OF THE INVENTION

This invention is generally related to forming a hydrophilic layer ofcoating for implantable medical devices, such as drug delivery vascularstents.

DESCRIPTION OF THE STATE OF THE ART

Stents are used not only as a mechanical intervention of vascularconditions but also as a vehicle for providing biological therapy. As amechanical intervention, stents act as scaffoldings, functioning tophysically hold open and, if desired, to expand the wall of thepassageway. Typically, stents are capable of being compressed, so thatthey can be inserted through small vessels via catheters, and thenexpanded to a larger diameter once they are at the desired location.Examples in patent literature disclosing stents that have been appliedin PTCA procedures include stents illustrated in U.S. Pat. No. 4,733,665issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S.Pat. No. 4,886,062 issued to Wiktor.

Biological therapy can be achieved by medicating the stents. Medicatedstents, e.g., stents with a coating that includes an agent, provide forthe local administration of a therapeutic substance at the diseasedsite. In order to provide an effective concentration at the treatedsite, systemic administration of useful medication often producesadverse or toxic side effects for the patient. Local delivery is apreferred method of treatment in that smaller total levels of medicationare administered in comparison to systemic dosages, but are concentratedat a specific site. Local delivery thus produces fewer side effects andachieves more favorable results.

Coatings on a medical device such as a stent are often desired to have asurface that can be modified to meet different biological or therapeuticneeds. Coatings formed of inert hydrophobic materials can have a surfacethat is hard to modify. One strategy is to incorporate hydrophilicmoieties into the coating. To incorporate hydrophilic moieties, thehydrophobic surface must be modified to make it compatible with thosemoieties or hydrophilic layers in a coating. Otherwise, the hydrophilicmoieties or layers of coating will either “wash off” or render a coatingwith poor mechanical integrity.

The embodiments described below address the above-identified problem.

SUMMARY

Provided herein is a method for modifying a hydrophobic surface of acoating by forming a hydrophilic surface layer on the hydrophobicsurface. The method includes contacting a substrate coating with asolution that includes a hydroxyl polymer (e.g. poly(vinyl alcohol)(PVOH) or a copolymer thereof) and a solvent to allow the hydroxylpolymer to adsorb onto, into, or both onto and into the substratecoating surface, removing the coating from the solution, and drying thecoating to form an adhesion layer that includes the hydroxyl polymer.

In some embodiments, the hydroxyl polymer can have a general formula asshown below:

where:

P can be H, CH₃, absence, ethylene vinyl alcohol, or a polymeric,oligomeric or monomeric unit(s). For example, P can be a biocompatiblepolymer such as polyolefin (e.g., polyethylene), poly(ethylene glycol)(PEG), poly(propylene oxide) (PPO), poly(vinylidene fluoride) (PVDF),poly(vinyl pyrrolidone) (PVP), poly((2-hydroxyl)ethyl methacrylate)(HEMA), poly(methyl methacrylate) (MMA), hyaluronic acid (HA),benzylated HA, or other biocompatible polymers;

R₁ and R₂ are independently H, CH₃ and CH₃CH₂;

R₃ can be H, CH₃, CH₃CH₂, and P; and

n is an integer ranging from 1 to about 1,000,000.

The layer comprising a hydroxyl polymer imparts hydrophilicity to thesubstrate coating. Hydrophilic surface layers can have differentthicknesses. In some embodiments, the hydrophilic surface layer can havea thickness ranging from about 20 angstroms to about 5 microns.

In some embodiments, the layer of hydroxyl polymer can optionallyinclude a bioactive agent. For example, the layer of hydroxyl polymercan be modified to conjugate with a bioactive agent to render the layerof hydroxyl polymer pro-healing or thrombo-resistant. In some otherembodiments, two or more layers of hydroxyl polymers can be formed on asubstrate coating, each of which can optionally include a bioactiveagent, that can be the same or different. Some exemplary agents include,but are not limited to, paclitaxel, docetaxel, estradiol, nitric oxidedonors, super oxide dismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), biolimus,tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), clobetasol, pimecrolimus,imatinib mesylate, midostaurin, prodrugs thereof, co-drugs thereof, or acombination thereof.

A medical device having the features described herein can be used totreat, prevent, or ameliorate a medical condition such asatherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissectionor perforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, claudication, anastomotic proliferation (for vein andartificial grafts), bile duct obstruction, ureter obstruction, tumorobstruction, and combinations thereof.

DETAILED DESCRIPTION

Provided herein is a method for modifying a hydrophobic surface of acoating by forming a hydrophilic surface layer on the hydrophobicsurface. The method includes contacting a substrate coating with asolution that includes a hydroxyl polymer (e.g. poly(vinyl alcohol)(PVOH) or a copolymer thereof) and a solvent to allow the hydroxylpolymer to adsorb onto, into, or both onto and into the substratecoating surface, removing the coating from the solution, and drying thecoating to form an adhesion layer that includes the hydroxyl polymer.

The hydrophilic surface layers formed according to the methods describedherein can have different thicknesses. In some embodiments, thehydrophilic layer can have a thickness ranging from about 20 angstromsto about 5 microns.

Coating Construct

A hydroxyl polymer in a solution can adsorb irreversibly ontohydrophobic surfaces, rendering them hydrophilic. The extent of polymeradsorption and thus hydrophilicity of the modified surface or coatingcan depend upon solution concentration, contact time, and the nature ofthe hydrophobic surface. Films that are adsorbed from dilute solutionsof the hydroxyl polymer tend to be thinner and more crystalline whilefilms that are adsorbed from more concentrated solutions tend to containmore loosely packed hydroxyl polymer chains that are less hydrogen boundto one another and thus more available to interact with surroundingaqueous media. This ability to tailor the hydrophilicity of a hydroxylpolymer surface enables a variety of surface modification chemistries.Additionally, the hydroxyl polymer is amenable to forming multiplepolymer layers. For example, a medical device having a surface ofhydrophobic polymer can be placed in a solution of a hydroxyl polymer toallow the hydroxyl polymer to adsorb onto the surface into a layer. Thedevice can then be removed from the solution, dried, and replaced in thesolution to allow the formation of another layer of the hydroxylpolymer. Following this route, multiple layers of hydroxyl polymer canbe built up on the surface. Moreover, varying the solution concentrationor contact time, can form multiple layers of hydroxyl polymers withdifferent properties.

Accordingly, in some embodiments, a medical device (e.g. stent) can bemade to have a coating that includes a layer of a hydroxyl polymercoated from a solution of a hydroxyl polymer. In some embodiments, thesolution of the hydroxyl polymer can be a dilute solution. The dilutesolution can have a concentration of the hydroxyl polymer ranging frome.g., about 20 to about 0.01 mol %. In some embodiments, the dilutesolution can have a concentration of the hydroxyl polymer about 0.01 mol% or less.

In yet other embodiments, a medical device (e.g. stent) can have acoating that includes a layer of a hydroxyl polymer coated from a moreconcentrated solution of the hydroxyl polymer. The more concentratedsolution can have a concentration of the hydroxyl polymer ranging fromabout 20 mol % to about 1 mol %.

In some embodiments, a medical device (e.g. stent) can have a coatingthat includes two or more layers of the hydroxyl polymer, one layercoated from a dilute solution of the hydroxyl polymer, the other coatedfrom a concentrated solution of the hydroxyl polymer. The dilutesolution of hydroxyl polymer can have a concentration ranging from e.g.,about 20 to about 0.01 mol %. In some embodiments, the dilute solutioncan have a concentration of the hydroxyl polymer about 0.01 mol % orless. The more concentrated solution can have a concentration of thehydroxyl polymer ranging from about 20 mol % to about 1 mol %.

In some further embodiments, a medical device (e.g. stent) can have acoating that includes two or more layers of hydroxyl polymers, one layercoated from a hydroxyl polymer solution in one solvent, the other coatedfrom a hydroxyl polymer solution in a different solvent. Differentsolvents can have different chemical and physical properties (e.g.different boiling points and/or polarity) so as to impart differentproperties to the layer of hydroxyl polymer.

In some further embodiments, a layer of hydroxyl polymer in a coating ona medical device (e.g., stent) can include one or more agents. Where thecoating includes two or more layers of hydroxyl polymer, each of thelayers of hydroxyl polymer can have an agent that can be the same ordifferent. The different agents can impart different biological and/ormedicinal properties to the coating. For example, a layer with aprohealing moiety coupled to the hydroxyl polymer can underlie anotherlayer of hydroxyl polymer used to facilitate a thrombo-resistantsurface.

In some embodiments, the hydroxyl polymer can be any polymer derivedfrom vinyl alcohol, having a general formula as shown below:

where:

P can be H, CH₃, absence, ethylene vinyl alcohol, or a polymeric,oligomeric or monomeric unit(s). For example, P can be a biocompatiblepolymer such as polyolefin (e.g., polyethylene), poly(ethylene glycol)(PEG), poly(propylene oxide) (PPO), poly(vinylidene fluoride) (PVDF),poly(vinyl pyrrolidone) (PVP), poly((2-hydroxyl)ethyl methacrylate)(HEMA), poly(methyl methacrylate) (MMA), hyaluronic acid (HA),benzylated HA, or other biocompatible polymers;

R₁ and R₂ are independently H, CH₃ and CH₃CH₂;

R₃ can be H, CH₃, CH₃CH₂, and P; and

n is an integer ranging from 1 to about 1,000,000.

The hydroxyl polymer can have different content of the repeating unitsderived from the vinyl alcohol monomer, ranging from about 100 mole % toabout 1.00 mole %, e.g., about 95 mole %, about 90 mole %, about 85 mole%, about 80 mole %, about 75 mole %, about 70 mole %, about 65 mole %,about 60 mole %, about 55 mole %, about 50 mole %, about 45 mole %,about 40 mole %, about 35 mole %, about 30 mole %, about 25 mole %,about 20 mole %, about 15 mole %, about 10 mole %, or about 5 mole %. Inone embodiment, the hydroxyl polymer is poly(ethylene-co-vinyl alcohol)(EVAL) having about 27 mole % ethylenyl units. In another embodiment,the hydroxyl polymer is PVOH.

Coating Solvents for Hydroxyl Polymers

A variety of solvents can be used to form the layer of hydroxyl polymerdescribed herein. Generally, the solvent is capable of dissolving PVOHand, if an agent is included in the PVOH, the agent. In someembodiments, where the layer of hydroxyl polymer is formed on top of adrug reservoir layer, the coating solvent for the layer of hydroxylpolymer preferably does not dissolve, or has a low solubility for thedrug (e.g., everolimus) in the drug reservoir.

Some representative coating solvents for coating the layer of hydroxylpolymer include, but are not limited to, water, dimethyl sulfoxide(DMSO), dimethyl acetamide (DMAC), alcohols such as methanol, ethanol,propanol, isopropanol, butanol, mixtures thereof, or a mixture thereofwith water.

Method of Forming a Layer of Hydroxyl Polymer

A layer of hydroxyl polymer can be formed on a coating on a medicaldevice (e.g., a stent) via established procedures, e.g., by dipping,soaking, spray coating, etc. The 1 hydroxyl polymer layer can have athickness, from about 25-50 angstrom to about 100 microns. In someembodiments, the layer of hydroxyl polymer can have a thickness of about0.1 to about 0.5 microns. Controlling the concentration of the PVOHsolution and the time of adsorption can control the thickness of thehydroxyl polymer layer. For example, the equilibrium thickness of PVOHdeposition onto a surface ofpoly(tetrafluoroethylene-co-hexafluoropropylene) (FEP) takesapproximately 24 hours when the surface is exposed to a water solutionof PVOH (Kozlov, M., Quarmyne, M., Chen, W. & McCarthy, T. J.,Adsorption of Poly(vinyl alcohol) onto hydrophobic substrates. A generalapproach for hydrophilizing and chemically activating surfaces.Macromolecules 36:6054-6059 (2003). However, a measurable layer ofhydroxyl polymer can be formed on the surface of a medical device inabout 9 minutes or less.

In some embodiments, there is a need to keep the drug (e.g., everolimus)in the reservoir layer from being released during deposition of thehydroxyl polymer. This can be accomplished by using the followingmeasures:

(1) saturating a soaking/coating solution of the hydroxyl polymer withthe drug,

(2) elevating the ionic strength of a coating solution of hydroxylpolymer so that its solubility for the drug is reduced,

(3) minimizing the solution volume of a hydroxyl polymer solution suchthat the amount of the drug that may be released from the reservoir isalso small, or

(4) selecting a solvent or solvent mixture capable of dissolving thehydroxyl polymer but not the drug and the reservoir layer.

“Small” as used for describing the solution volume of a hydroxyl polymersolution refers to a volume of the solution sufficient to cover thedevice. In some embodiments, a small volume is less than about 1 mL; inthese or other embodiments a small volume is about 750 μL.

During the drying process, the hydroxyl polymer can partiallycrystallize. In some embodiments, placing the layer of hydroxyl polymerin a high humidity atmosphere and annealing it can promote additionalcrystallization. The hydroxyl polymer layer can affect the drug releaserate from the device depending on the drug properties. For everolimus,the drug release rate is not expected to be greatly affected by thehydroxyl polymer layer.

Surface Modification of Layer of Hydroxyl Polymer

In some embodiments, pendant or functional group attachment to the layerof hydroxyl polymer can modify the hydrophilic surface. For example,several strategies have been established to conjugate a chosen compoundto the mildly reactive hydroxyl groups in the hydroxyl polymer.

In one embodiment, polyethylene glycol (PEG) can attach to the hydroxylpolymer. As attached, PEG can serve as a spacer between the hydroxylpolymer surface and an agent such as a peptide, protein, or a drugmolecule. To serve as a spacer, one end of PEG can be, e.g., an aminegroup protected with a protective group such as methoxycarbonyl (MOC) or9-fluorenylmethyoxycarbonyl (FMOC), while the other end of PEG can beany of the following groups:

(a) a carboxylic acid or N-hydroxysuccinimide (NHS)— coupling of the PEGto the hydroxyl polymer surface can be readily accomplished in thepresence of N,N′-carbonyldiimidazole or dicyclohexylcarbodiimide (DCC),which are commercially available;

(b) an acid chloride—PEG can be easily functionalized using acryloylchloride; and

(c) a vinyl sulphone—coupling of PEG to the surface of the hydroxylpolymer can be achieved under acidic conditions.

Upon completion of attaching the PEG to the surface of the hydroxylpolymer, the protecting group on the PEG molecule can be removed,yielding a hydroxyl polymer surface with dangling, amine-terminated, PEGchains. The amine group can be used to conjugate with a bioactive agentsuch as a pro-healing agent. Alternatively, the protected end of PEG canbe an aldehyde or a protected carboxylic acid group. Upon attaching theother end of PEG to the hydroxyl polymer surface, the protective groupscan be removed, yielding a hydroxyl polymer surface with dangling,aldehyde- or carboxylic-acid-terminated PEG chains. The aldehyde orcarboxylic acid groups then can conjugate with an agent such as a drugmolecule.

Chemistries of attaching different spacers to a surface of the hydroxylpolymer are well documented in the art. Chemistries for conjugating thespacer to an agent such as a peptide or a drug molecule are welldocumented in the art, as well. (see, e.g., Cabral, J. M. S; Kennedy, J.F. In Protein Immobilization, Fundamental and Applications; Taylor, R.F., Ed; Marcel Dekker, Inc.: New York, 1991; Chapter 3, pp 74).

In some embodiments, the surface of the hydroxyl polymer can be mademore stable by including in the surface layer a material capable ofminimizing the interfacial energy between the layer of hydroxyl polymerand the hydrophobic coating or layer underneath. Such a materialgenerally has a hydrophobic section and a hydrophilic section in themolecule. Examples of such materials include, but are not limited to,poly(propylene oxide-co-vinyl alcohol) (PPO-co-PVOH), or poly(vinylidenefluoride-co-vinyl alcohol) (PVDF-co-PVOH). In some embodiments thematerial is polymeric. In some embodiments, the surface of the hydroxylpolymer can be made more stable by crosslinking with a crosslinkingagent such as glutaldehyde.

In some embodiments, the hydroxyl polymer layer can be furtherstabilized by exposing the layer to freeze-thaw cycles after coating.

In some other embodiments, the layer of hydroxyl polymer can bestabilized by forming a partial interpenetrating network (P-IPN) orsemi-interpenetrating network (S-INP) of PVOH. The P-IPN or S-IPN can beformed by applying a hydroxyl polymer in a solvent selected to swell thesubstrate coating (e.g., a drug delivery coating or a top coating).Hydrogen bonding between molecules of PVOH in the substrate allows theformation of P-INP or S-INP morphology, thus stabilizing the hydroxylpolymer surface layer. In one embodiment, these interpenetratingnetworks are formed similarly as described above except that networksare additionally curing by exposure to an e-beam, UV, or plasma to graftthe hydroxyl polymer or block copolymer to the substrate coating. Curingcan be accomplished with or without a curing agent such as maleic orfumaric acid.

Some exemplary PVOH block copolymers include, but are not limited to,PVOH-co-HEMA, PVOH-co-MMA-HEMA, or PVOH-HA-benzylated.

In some embodiments, the hydroxyl polymer is EVAL. EVAL is commerciallyavailable in several grades. The grade that most closely resembles thebehavior of PVOH is the one with the lowest ethylene content, which isthe L-Series EVAL from EVALCA (which contains 27 mole % ethylene). Thispolymer is soluble in organic solvents such as DMSO, DMAC, and somealcohols. However, it will not dissolve in hot water (unlike pure PVOH).Consequently, this 20-mole %-ethylene EVAL can be spray or dip coatedonto a substrate coating. After drying, the ethylene component maymigrate to the surface. But, in an aqueous or a very polar solvent, theL-series EVAL coating will swell, and the surface will reorient morehydroxyl groups to the surface. The L-series EVAL's equilibrium waterabsorption is greater than 10% (w/w), which indicates that the L-seriesEVAL in a coating can easily swell in an aqueous environment to reorientthe OH and CH₃ groups.

Substrate Coating

One or multiple layers of a hydroxyl polymer can be formed on thesurface of any substrate coating. The substrate coating can include oneor more biocompatible polymer(s). The biocompatible polymer can bebiodegradable (both bioerodable or bioabsorbable) or nondegradable.Representative biocompatible polymers include, but are not limited to,poly(ester amide), polyhydroxyalkanoates (PHA),poly(3-hydroxyalkanoates) such as poly(3-hydroxypropanoate),poly(3-hydroxybutyrate), poly(3-hydroxyvalerate),poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate) andpoly(3-hydroxyoctanoate), poly(4-hydroxyalkanaote) such aspoly(4-hydroxybutyrate), poly(4-hydroxyvalerate),poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),poly(4-hydroxyoctanoate) and copolymers including any of the3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein orblends thereof, poly(D,L-lactide), poly(L-lactide), polyglycolide,poly(D,L-lactide-co-glycolide), poly(L-lactide-co-glycolide),polycaprolactone, poly(lactide-co-caprolactone),poly(glycolide-co-caprolactone), poly(dioxanone), poly(ortho esters),poly(anhydrides), poly(tyrosine carbonates) and derivatives thereof,poly(tyrosine ester) and derivatives thereof, poly(imino carbonates),poly(glycolic acid-co-trimethylene carbonate), polyphosphoester,polyphosphoester urethane, poly(amino acids), polycyanoacrylates,poly(trimethylene carbonate), poly(iminocarbonate), polyurethanes,polyphosphazenes, silicones, polyesters, polyolefins, polyisobutyleneand ethylene-alphaolefin copolymers, acrylic polymers and copolymers,vinyl halide polymers and copolymers, such as polyvinyl chloride,polyvinyl ethers, such as polyvinyl methyl ether, polyvinylidenehalides, such as polyvinylidene chloride, polyacrylonitrile, polyvinylketones, polyvinyl aromatics, such as polystyrene, polyvinyl esters,such as polyvinyl acetate, copolymers of vinyl monomers with each otherand olefins, such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers, polyamides, such as Nylon 66 and polycaprolactam, alkydresins, polycarbonates, polyoxymethylenes, polyimides, polyethers,poly(glyceryl sebacate), poly(propylene fumarate), poly(n-butylmethacrylate), poly(sec-butyl methacrylate), poly(isobutylmethacrylate), poly(tert-butyl methacrylate), poly(n-propylmethacrylate), poly(isopropyl methacrylate), poly(ethyl methacrylate),poly(methyl methacrylate), epoxy resins, polyurethanes, rayon,rayon-triacetate, cellulose acetate, cellulose butyrate, celluloseacetate butyrate, cellophane, cellulose nitrate, cellulose propionate,cellulose ethers, carboxymethyl cellulose, polyethers such aspoly(ethylene glycol) (PEG), copoly(ether-esters) (e.g. PEO/PLA),polyalkylene oxides such as poly(ethylene oxide), poly(propylene oxide),poly(ether ester), polyalkylene oxalates, polyphosphazenes, phosphorylcholine, choline, poly(aspirin), polymers and co-polymers of hydroxylbearing monomers such as HEMA, hydroxypropyl methacrylate (HPMA),hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG methacrylate,2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone(VP), carboxylic acid bearing monomers such as methacrylic acid (MA),acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),biomolecules such as collagen, chitosan, alginate, fibrin, fibrinogen,cellulose, starch, collagen, dextran, dextrin, fragments and derivativesof hyaluronic acid, heparin, fragments and derivatives of heparin,glycosamino glycan (GAG), GAG derivatives, polysaccharide, elastin,chitosan, alginate, or combinations thereof. In some embodiments, thesubstrate coating described herein can exclude any one of theaforementioned polymers.

As used herein, the terms poly(D,L-lactide), poly(L-lactide),poly(D,L-lactide-co-glycolide), and poly(L-lactide-co-glycolide) can beused interchangeably with the terms poly(D,L-lactic acid), poly(L-lacticacid), poly(D,L-lactic acid-co-glycolic acid), or poly(L-lacticacid-co-glycolic acid), respectively.

In some embodiments, the substrate coating can further include abiobeneficial material. The biobeneficial material can be polymeric ornon-polymeric. The biobeneficial material is preferably substantiallynon-toxic, non-antigenic and non-immunogenic. A biobeneficial materialis one that enhances the biocompatibility of a device by beingnon-fouling, hemocompatible, actively non-thrombogenic, oranti-inflammatory, all without depending on the release of apharmaceutically active agent.

Representative biobeneficial materials include, but are not limited to,polyethers such as poly(ethylene glycol), copoly(ether-esters) (e.g.PEO/PLA), polyalkylene oxides such as poly(ethylene oxide),poly(propylene oxide), poly(ether ester), polyalkylene oxalates,polyphosphazenes, phosphoryl choline, choline, poly(aspirin), polymersand co-polymers of hydroxyl bearing monomers such as hydroxyethylmethacrylate (HEMA), hydroxypropyl methacrylate (HPMA),hydroxypropylmethacrylamide, poly(ethylene glycol) acrylate (PEGA), PEGmethacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinylpyrrolidone (VP), carboxylic acid bearing monomers such as methacrylicacid (MA), acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen,dextran, dextrin, hyaluronic acid, fragments and derivatives ofhyaluronic acid, heparin, fragments and derivatives of heparin,glycosamino glycan (GAG), GAG derivatives, polysaccharide, elastin,chitosan, alginate, silicones, PolyActive™, and combinations thereof. Insome embodiments, the substrate coating can exclude any one of theaforementioned polymers.

The term PolyActive™ refers to a block copolymer having flexiblepoly(ethylene glycol) and poly(butylene terephthalate) blocks(PEGT/PBT). PolyActive™ is intended to include AB, ABA, BAB copolymershaving such segments of PEG and PBT (e.g., poly(ethyleneglycol)-block-poly(butyleneterephthalate)-block poly(ethylene glycol)(PEG-PBT-PEG).

In a preferred embodiment, the biobeneficial material can be a polyethersuch as poly (ethylene glycol) (PEG) or polyalkylene oxide.

In some embodiment, one or multiple layers of a hydroxyl polymer can beformed on the surface of a medical device formed of a polymer (e.g., adurable or bioabsorbable stent) without a coating.

Bioactive Agents

In some embodiments, the substrate coating and/or the layer of hydroxylpolymer can include one or more bioactive agents. The bioactive agentscan be any bioactive agent that is therapeutic, prophylactic, ordiagnostic. These agents can have anti-proliferative oranti-inflammatory properties or can have other properties such asantineoplastic, antiplatelet, anti-coagulant, anti-fibrin,antithrombonic, antimitotic, antibiotic, antiallergic, and antioxidantproperties. These agents can be cystostatic agents, agents that promotethe healing of the endothelium such as NO releasing or generatingagents, agents that attract endothelial progenitor cells, or agents thatpromote the attachment, migration and proliferation of endothelial cells(e.g., natriuretic peptide such as CNP, ANP or BNP peptide or an RGD orcRGD peptide), while quenching smooth muscle cell proliferation.Examples of suitable therapeutic and prophylactic agents includesynthetic inorganic and organic compounds, proteins and peptides,polysaccharides and other sugars, lipids, and DNA and RNA nucleic acidsequences having therapeutic, prophylactic or diagnostic activities.Nucleic acid sequences include genes, antisense molecules that bind tocomplementary DNA to inhibit transcription, and ribozymes. Some otherexamples of other bioactive agents include antibodies, receptor ligands,enzymes, adhesion peptides, blood clotting factors, inhibitors or clotdissolving agents such as streptokinase and tissue plasminogenactivator, antigens for immunization, hormones and growth factors,oligonucleotides such as antisense oligonucleotides and ribozymes andretroviral vectors for use in gene therapy. Examples ofanti-proliferative agents include rapamycin and its functional orstructural derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),and its functional or structural derivatives, paclitaxel and itsfunctional and structural derivatives. Examples of rapamycin derivativesinclude methyl rapamycin (ABT-578), 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.Examples of paclitaxel derivatives include docetaxel. Examples ofantineoplastics and/or antimitotics include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorssuch as Angiomax (Biogen, Inc., Cambridge, Mass.), calcium channelblockers (such as nifedipine), colchicine, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxidedonors, super oxide dismutases, super oxide dismutase mimetic,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), estradiol,anticancer agents, dietary supplements such as various vitamins, and acombination thereof. Examples of anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatory agents include tacrolimus,dexamethasone, clobetasol, combinations thereof. Examples of suchcytostatic substance include angiopeptin, angiotensin converting enzymeinhibitors such as captopril (e.g. Capoten® and Capozide® fromBristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril(e.g. Prinivil® and Prinzide® from Merck & Co., Inc., WhitehouseStation, N.J.). An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents that may beappropriate include alpha-interferon, pimecrolimus, imatinib mesylate,midostaurin, bioactive RGD, and genetically engineered endothelialcells. The foregoing substances can also be used in the form of prodrugsor co-drugs thereof. The foregoing substances also include metabolitesthereof and/or prodrugs of the metabolites. The foregoing substances arelisted by way of example and are not meant to be limiting. Other activeagents that are currently available or that may be developed in thefuture are equally applicable.

The dosage or concentration of the bioactive agent required to produce afavorable therapeutic effect should be less than the level at which thebioactive agent produces toxic effects and greater than the level atwhich non-therapeutic results are obtained. The dosage or concentrationof the bioactive agent can depend upon factors such as the particularcircumstances of the patient, the nature of the trauma, the nature ofthe therapy desired, the time over which the ingredient administeredresides at the vascular site, and if other active agents are employed,the nature and type of the substance or combination of substances.Therapeutic effective dosages can be determined empirically, for exampleby infusing vessels from suitable animal model systems and usingimmunohistochemical, fluorescent or electron microscopy methods todetect the agent and its effects, or by conducting suitable in vitrostudies. Standard pharmacological test procedures to determine dosagesare understood by one of ordinary skill in the art.

Examples of Implantable Device

As used herein, an implantable device may be any suitable medicalsubstrate that can be implanted in a human or veterinary patient.Examples of such implantable devices include self-expandable stents,balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts),heart valve prostheses, cerebrospinal fluid shunts, pacemakerelectrodes, catheters, and endocardial leads (e.g., FINELINE andENDOTAK, available from Guidant Corporation, Santa Clara, Calif.),anastomotic devices and connectors, orthopedic implants such as screws,spinal implants, and electro-stimulatory devices. The underlyingstructure of the device can be of virtually any design. The device canbe made of a metallic material or an alloy such as, but not limited to,cobalt chromium alloy (ELGILOY), stainless steel (316 L), high nitrogenstainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, “MP35N,”“MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable (e.g., bioabsorbable stent) or biostable polymers couldalso be used with the embodiments of the present invention.

Method of Use

Preferably, the medical device is a stent. The stent described herein isuseful for a variety of medical procedures, including, by way ofexample, treatment of obstructions caused by tumors in bile ducts,esophagus, trachea/bronchi and other biological passageways. A stenthaving the above-described coating is particularly useful for treatingdiseased regions of blood vessels caused by lipid deposition, monocyteor macrophage infiltration, or dysfunctional endothelium or acombination thereof, or occluded regions of blood vessels caused byabnormal or inappropriate migration and proliferation of smooth musclecells, thrombosis, and restenosis. Stents may be placed in a wide arrayof blood vessels, both arteries and veins. Representative examples ofsites include the iliac, renal, carotid and coronary arteries.

For implantation of a stent, an angiogram is first performed todetermine the appropriate positioning for stent therapy. An angiogram istypically accomplished by injecting a radiopaque contrasting agentthrough a catheter inserted into an artery or vein as an x-ray is taken.A guidewire is then advanced through the lesion or proposed site oftreatment. Over the guidewire is passed a delivery catheter that allowsa stent in its collapsed configuration to be inserted into thepassageway. The delivery catheter is inserted either percutaneously orby surgery into the femoral artery, radial artery, brachial artery,femoral vein, or brachial vein, and advanced into the appropriate bloodvessel by steering the catheter through the vascular system underfluoroscopic guidance. A stent having the above-described coating maythen be expanded at the desired area of treatment. A post-insertionangiogram may also be utilized to confirm appropriate positioning.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A medical device having a layer formed according to a methodcomprising: providing a composition comprising a hydroxyl polymer;providing a medical device comprising a coating; forming a layer of thecomposition on the coating, attaching a spacer to the layer to generatedangling functional-group-terminated spacer chains, and conjugating abioactive agent to the spacer via the functional group; wherein thehydroxyl polymer has a structure of

where: P is H, CH₃, absence, ethylene vinyl alcohol, or a polymeric,oligomeric or monomeric unit; R₁ and R₂ are independently H, CH₃ andCH₃CH₂; R₃ is be H, CH₃, CH₃CH₂, and P; and n is an integer ranging from1 to about 1,000,000.
 2. The medical device of claim 1 wherein formingcomprises absorbing the hydroxyl polymer onto, into or both onto andinto the coating.
 3. The medical device of claim 1 wherein P is selectedfrom the group consisting of CH₃, polyolefin (e.g., polyethylene),poly(ethylene glycol) (PEG), poly(propylene oxide) (PPO),poly(vinylidene fluoride) (PVDF), poly(vinyl pyrrolidone) (PVP),poly((2-hydroxyl)ethyl methacrylate) (HEMA), poly(methyl methacrylate)(MMA), hyaluronic acid (HA), benzylated HA, poly(ethylene-co-vinylalcohol) (EVAL), and combinations thereof.
 4. The medical device ofclaim 1 wherein the hydroxyl polymer is poly(vinyl alcohol) (PVOH) orEVAL.
 5. The medical device of claim 1 further comprising forming anadditional layer comprising the hydroxyl polymer.
 6. The medical deviceof claim 2 wherein the composition layer has a thickness from 20angstroms to about 5 microns.
 7. The medical device of claim 5 whereinthe composition layer and the additional layer independently have athickness from 20 angstroms to about 5 microns.
 8. The medical device ofclaim 1 wherein the coating comprises a bioactive agent.
 9. The medicaldevice of claim 8 wherein the agent is selected from the groupconsisting of paclitaxel, docetaxel, estradiol, 17-beta-estradiol,nitric oxide donors, super oxide dismutases, super oxide dismutasesmimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),biolimus, tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), clobetasol, pimecrolimus,imatinib mesylate, midostaurin, prodrugs thereof, co-drugs thereof, anda combination thereof.
 10. The medical device of claim 1, wherein thehydroxyl polymer is PVOH, and wherein the composition further comprisesa block copolymer comprising PVOH.
 11. The medical device of claim 1,wherein the hydroxyl polymer is PVOH, and wherein the composition layerfurther comprises a block copolymer comprising PVOH.
 12. The medicaldevice of claim 1 wherein the hydroxyl polymer is a block copolymerselected from the group consisting of poly(propylene oxide-co-vinylalcohol) (PPO-co-PVOH), poly(vinylidene fluoride-co-vinyl alcohol)(PVDF-co-PVOH), EVAL, and combinations thereof.
 13. The medical deviceof claim 1, wherein the method further comprises treating thecomposition layer to freeze-thaw cycle(s) to increase the stability ofthe layer.
 14. The medical device of claim 1 wherein forming comprises:swelling the coating with the solution of the composition, and formingthe composition layer on the coating, wherein the composition isdissolved in a solvent capable of partially swelling the coating. 15.The medical device of claim 13, wherein the method further comprisescuring the composition layer to graft the layer to the coating.
 16. Themedical device of claim 14 wherein the composition layer furthercomprises maleic acid, fumaric acid, or combinations thereof.
 17. Themedical device of claim 14 wherein curing is achieved by e-beam, UVirradiation or plasma exposure.
 18. The medical device of claim 8wherein the composition layer further comprises a bioactive agent thatis the same as the bioactive agent in the coating or different from thebioactive agent in the coating.
 19. The medical device of claim 16wherein the bioactive agent is paclitaxel, docetaxel, estradiol,17-beta-estradiol, nitric oxide donors, super oxide dismutases, superoxide dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), biolimus, tacrolimus, dexamethasone, rapamycin,rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), clobetasol, pimecrolimus,imatinib mesylate, midostaurin, prodrugs thereof, co-drugs thereof, anda combination thereof.
 20. The medical device of claim 1 wherein thehydroxyl polymer is PVOH, and the method further comprises exposing thelayer to a humid environment to promote additional crystallization ofthe PVOH.
 21. The medical device of claim 1, wherein the method furthercomprises including a material capable of minimizing the interfacialenergy between the layer of hydroxyl polymer and the coating beneath soto make the surface of the hydroxyl polymer more stable; wherein thematerial is poly(propylene oxide-co-vinyl alcohol) or poly(vinylidenefluoride-co-vinyl alcohol); or crosslinking the hydroxyl polymer usingglutaldehyde.
 23. The medical device of claim 1 wherein the spacer ispoly(ethylene glycol) (PEG), the functional group is amine, carboxylicacid, or aldehyde, and wherein the bioactive agent is a pro-healingagent, an antithrombogenic agent, a non-fouling agent, or combinationsthereof.
 24. The medical device of claim 1 wherein the hydroxyl polymeris poly(vinyl alcohol-co-(2-hydroxyl)ethyl methacrylate) (PVOH-co-HEMA),poly(vinyl alcohol-co-methyl methacrylate-co-(2-hydroxyl)ethylmethacrylate) (PVOH-co-MMA-co-HEMA), poly(vinyl alcohol-co-hyaluronicacid) (PVOH-co-HA), poly(vinyl alcohol-co-benzylated hyaluronic acid)(PVOH-co-HA-Bz), EVAL or combinations thereof.
 25. The medical device ofclaim 1 which is a stent.
 26. The medical device of claim 24 which is astent.
 27. The medical device of claim 1 which is an absorbable stent.28. The medical device of claim 24 which is an absorbable stent.